Modern clinical research on LSD

Liechti reviews modern clinical research on lysergic acid diethylamide (LSD), focusing on controlled clinical studies published in the past 25 years. The article situates recent work against the much larger historical literature from the 1950s–1970s, which has been summarised elsewhere, and notes that modern research is resurging alongside renewed work on other serotonergic hallucinogens such as psilocybin and DMT. The review aims to synthesise findings from all recent controlled clinical LSD studies identified through Medline and clinicaltrials.gov searches, with attention to clinical pharmacology, subjective and objective effects, neuroimaging results, safety, and therapeutic potential. By collating these modern data, the paper seeks to clarify what is known and what remains uncertain about LSD's mechanisms, acute effects, and possible roles in psychiatry.

The paper is a narrative review of contemporary clinical studies of LSD rather than a new primary trial. Liechti states that ‘‘all modern controlled clinical studies of LSD published in the past 25 years’’ were included based on searches of Medline and clinicaltrials.gov. The extracted text does not provide a full systematic review protocol, explicit inclusion/exclusion criteria, date limits for the searches, or a formal risk-of-bias assessment, and it does not present a PRISMA-style flow diagram. Where individual studies are discussed, the review reports their designs and sample characteristics as presented in the original papers (for example, randomised, double-blind placebo-controlled experimental studies in healthy volunteers and a small randomised trial in patients with life-threatening illness). Key methodological details from the cited studies that are summarised include dose regimens (oral 100 μg and 200 μg, intravenous 75 μg in some studies), psychometric instruments used (for example the 5D-ASC and visual analogue scales), physiological and endocrine measures, imaging modalities (resting-state fMRI, arterial spin labelling, magnetoencephalography), and the use of psychotherapeutic support in patient studies. The review does not present pooled quantitative meta-analytic methods or meta-analytic models.

Scope and included studies: Modern controlled clinical work on LSD comprised a small set of studies in healthy volunteers and a single modern patient trial; the abstract notes five recent healthy-participant studies and one patient study. Experimental work examined subjective effects, physiology, endocrine responses, sensorimotor gating, emotional processing, and brain function with multimodal neuroimaging. Receptor pharmacology and mechanism: LSD binds strongly to multiple receptors, notably serotonin 5-HT2A and 5-HT1A, and also has affinity for 5-HT2C, dopamine D2, and α-adrenergic receptors. It is a partial agonist at 5-HT2A receptors, and 5-HT2A activation is identified as the primary mediator of hallucinogenic effects; however, downstream signalling and the full cascade linking receptor binding to phenomenology remain incompletely defined. The review highlights differences between LSD and other serotonergic hallucinogens, including higher potency at 5-HT2A and additional adrenergic and dopaminergic receptor interactions. Subjective effects: In controlled settings LSD produced predominantly positive acute subjective effects. At 200 μg oral, mean group ratings of ‘good drug effect’ and ‘drug liking’ on visual analogue scales reached about 90% of maximum. Mean group increases in ‘negative drug effect’ and ‘fear’ were modest (<25%), although roughly half of subjects showed transiently larger negative responses during 200 μg sessions. LSD elevated scores on all dimensions of the 5D-ASC (an instrument measuring altered states of consciousness), with characteristic effects including blissful state, audiovisual synesthesia, altered meaning of perceptions, derealisation/depersonalisation experienced positively, and mystical-type experiences. A 200 μg oral dose produced greater bliss, altered meaning, and insightfulness than 100 μg; intravenous 75 μg produced effects similar to 100 μg oral but lower than 200 μg. LSD also increased feelings of closeness, openness, trust and suggestibility; music was reported to acquire enhanced emotional meaning under LSD. Autonomic, endocrine and safety signals: Physiologically, LSD produced modest sympathomimetic effects with increases in blood pressure, heart rate, body temperature and pupil size; these were less pronounced than with MDMA or typical stimulants. Endocrine measures showed acute increases in plasma cortisol, prolactin, oxytocin and epinephrine, without increases in norepinephrine, testosterone or progesterone. In controlled medical settings no severe drug-related adverse events were reported in the modern studies; profound panic or medical complications were not observed. The review discusses flashbacks and hallucinogen persisting perception disorder (HPPD) as primarily issues in recreational use, with HPPD described as rare and mostly linked to unsupervised consumption. Sensorimotor gating and cognition: LSD disrupted prepulse inhibition (PPI) of the startle response in animals and humans, a deficit resembling aspects of schizophrenia in sensorimotor gating. Cognitive disorganisation and delusional thinking increased with intravenous 75 μg in one study, but the overall acute experience was reported as predominantly positive in the majority of subjects. LSD impaired recognition of sad and fearful facial expressions, enhanced emotional empathy, but also impaired identification of complex emotions. Neuroimaging and electrophysiology: Resting-state fMRI studies showed that LSD decreased within-network functional integrity (for example in the default mode network, DMN) while increasing between-network connectivity. Thalamocortical functional connectivity was increased, and enhanced connectivity of primary visual cortex (V1) with widespread regions correlated with subjective visual hallucinations. Global measures of brain ‘‘entropy’’ (reduced predictability of resting fMRI time series) were increased under LSD and this acute increase correlated with greater trait openness assessed 14 days later. Reduced DMN integrity correlated with subjective ratings of ego dissolution, and decreases in parahippocampal connectivity related to altered meaning and ego dissolution. Arterial spin labelling showed greater cerebral blood flow in visual cortex linked to complex imagery, and magnetoencephalography revealed decreased oscillatory power during eyes-closed rest. The authors caution that many imaging findings derive from small studies and may be influenced by vascular effects of LSD. Pharmacokinetics and duration: Oral LSD pharmacokinetics were characterised for 100 μg and 200 μg doses: Tmax about 1.5 h, elimination half-life around 3 h, with plasma detectability up to 12–24 h and linear, dose-proportional kinetics up to 12 h. Subjective effects peaked around 2.5 h and lasted approximately 8 h after 100 μg and 12 h after 200 μg. Intravenous 75 μg produced subjective peaks at 45–120 min and effects lasting 7–8 h. No evidence of acute tolerance after single doses was reported, though tolerance with repeated daily dosing has been observed historically. Mid- and long-term effects: In healthy-subject studies, single LSD administrations increased optimism and trait openness at two weeks in one report, and acute increases in brain entropy and ego-dissolution during music were associated with greater openness. These findings are preliminary and complicated by participants' prior LSD use in some samples. Epidemiological data cited suggested that lifetime use of classic hallucinogens is associated with lower psychological distress and suicidality, but causality is not established. Clinical patient data: Only one modern controlled patient trial of LSD is described. Eleven patients with anxiety associated with life-threatening disease (eight with cancer) participated; eight received 200 μg LSD twice, and three received an active low-dose placebo (20 μg) twice, with an open-label crossover to 200 μg after the first blinded phase. At baseline many had elevated anxiety, and several had generalized anxiety disorder or major depression. The trial reported a statistically significant decrease in state-trait anxiety inventory (STAI) scores two months after the two LSD sessions compared with baseline; STAI did not decrease in the small placebo group, but the control arm was too small for robust statistical comparison. Non-significant improvements in depression and quality of life were reported, and a 12-month follow-up in nine patients suggested sustained anxiety reductions and no lasting adverse reactions, but lacked a control group. No drug-related severe adverse effects, prolonged psychoses, or panic reactions were reported in this trial.

Liechti interprets the modern clinical data as showing that LSD produces robust, predominantly positive altered-state experiences in controlled settings that are mediated primarily by 5-HT2A receptor activation. Neuroimaging and neurophysiological results are presented as preliminary mechanistic evidence that LSD decreases the integrity of intrinsic brain networks while increasing connectivity between normally segregated networks, increases thalamocortical and visual system connectivity, and raises global brain entropy; some of these neural changes correlate with subjective phenomena such as ego dissolution, visual hallucinations and later increases in openness. The review positions these findings within earlier literature on serotonergic hallucinogens, noting similarities with psilocybin and ayahuasca on several behavioural, endocrine and neural endpoints, but also emphasising pharmacological distinctions of LSD (for example, additional receptor affinities and longer duration). The authors suggest that several acute effects of LSD—reduced amygdala reactivity to negative stimuli, increased feelings of closeness and trust, and facilitation of emotional empathy—could plausibly aid psychotherapeutic processing in clinical contexts. Key limitations acknowledged include the small number of modern studies and small sample sizes, especially for imaging work where chance findings are possible and vascular confounds may influence BOLD-based measures. The single modern patient trial is underpowered and lacked a robust control, limiting inferences about therapeutic efficacy. Other uncertainties highlighted are the unresolved downstream signalling pathways of 5-HT2A activation, the need for direct comparisons with psilocybin and DMT, absence of systematic dose–response data for many outcomes, and difficulty disentangling the pharmacological effects of LSD from the effects of psychotherapeutic context. For future research the authors call for larger, methodologically rigorous clinical trials to define therapeutic benefits and optimal indications, neuroimaging work to link acute brain changes with longer-term clinical outcomes, and studies that disentangle substance effects from psychotherapeutic components. Practical barriers cited include regulatory scheduling that impedes research and high costs driven by overregulation; the review also notes that industry funding is unlikely and that careful clinical study is needed so patients do not seek unregulated treatments.

Liechti concludes that a small number of supervised administrations of LSD in therapeutic settings may hold potential benefit for patients with anxiety related to severe illness, depression or addiction. The paper advocates for more methodologically sound research into the psychological and biological mechanisms and clinical utility of LSD, emphasising that professionals should study these approaches so vulnerable patients do not resort to unproven, unregulated alternatives.